The present invention relates to a neurotrophin production/secretion promoting agent which comprises an azole derivative or a salt thereof and is useful in the treatment or prevention of neuropathy and so forth, and to novel thiazole derivatives and oxazole derivatives having neurotrophin production/secretion promoting activity.
Neurotrophin is a generic term denoting nerve growth factor (NGF) gene families, meaning proteins which play an important role in the differentiation and functional homeostasis of central and peripheral nerve cells, synapse formation, and regeneration or repair of injured nerve cells. In addition to NGF, so far discovered in mammals are brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5) (while neurotrophin-6 (NT-6) has been discovered in fish, it is not known whether this exists in mammals as well). While these are similar in structure and in physiological activity, it is known that they differ in specificity to responding neurons. On the other hand, TrkA, TrkB and TrkC, which are trk family gene products, have been identified as neurotrophin receptors. NGF has high affinity for TrkA, BDNF and NT-4/5 have high affinity for TrkB, and NT-3 has high affinity for TrkC. The complicated actions of neurotrophins on the nervous system are considered to result from the functions, distributions and expression regulating mechanisms involved of neurotrophins and their receptors.
The possibility of clinical application of neurotrophins has been suggested based on the diversity of their actions on the nervous system. In fact, in animal experiments, it has been revealed that NGF, upon intracranial administration, improves the memory and ability to learn and prevents death of neurons due to brain ischemia (Brain Res., vol. 293, p. 305(1985); Science, vol. 235, p. 214 (1986); Proc. Natl. Acad. Sci. USA, vol. 83, p. 9231 (1986); and etc.). Further, it was confirmed by Lans Olsson et al. that direct injection of NGF into the brain of patients with Alzheimer""s disease resulted in amelioration of symptoms of dementia (1991 Symposium on Alzheimer""s Disease). Further, patients with diabetic neuropathy show a decreased serum NGF level and, in animal experiments, the pathology of diabetic neuropathy is improved by administration of NGF (Acta Neurol. Scand., vol. 81, p. 402 (1990); Brain Res., vol. 634, p. 7 (1994)) and, based on these and other findings, NGF is considered to effectively act on peripheral nervous system diseases as well as the central nervous system diseases. On the other hand, it is known that when the rat sciatic nerve is injured, Schwann cells transiently synthesize and secrete NGF and thereafter synthesize and secrete BDNF over a long period (J. Cell Biol., vol. 119, p. 45 (1992)). It is further known that BDNF, when intramuscularly administered to wobbler mice genetically developing motor nerve degeneration, prevents the nerve degeneration (Neurology, 50 (4S) A 246 (1998)), that it shows a protective effect on the motor nerve degeneration and nerve cells death in rats (40th Meeting of the Japanese Neurochemical Society, 238 (1997); 15th Meeting of the International Society for Neurochemistry, S85 (1995)) and that it shows a protective effect on motor functions and sensory nerve cells in an acrylamide neuropathy model (60th Meeting of the Japanese Pharmacological Society, P-532, 1996).
In view of these findings, NGF is currently under clinical investigation as a therapeutic agent for peripheral neuropathy caused by cancer chemotherapy or diabetes mellitus (Genentech), and BDNF as a therapeutic agent for nerve degeneration diseases or amyotrophic lateral sclerosis (ALS) (Sumitomo Pharmaceutical, Regeneron).
However, these neurotrophins are macromolecular proteins each having a molecular weight of 10,000 or more and it is known that applying these neurotrophins as therapeutic agents can lead to problems, such as limited methods of administration and safety problems. Therefore, searching for low molecular weight compounds capable of promoting the production/secretion of neurotrophins in a specific tissue is of great significance in developing prophylactic/therapeutic agents for diseases of the central or peripheral nervous system. Low molecular weight compounds hitherto known to have NGF production/secretion promoting activity include catechol derivatives (Furukawa, Y., J. Biol. Chem., vol. 261, p. 6039 (1986); JP Kokai S63-83020; JP Kokai S63-156751; JP Kokai H02-53767; JP Kokai H02-104568; JP Kokai H02-149561; JP Kokai H03-99046; JP Kokai H03-83921; JP Kokai H03-86853; JP Kokai H05-32646), quinone derivatives (JP Kokai H03-81218; JP Kokai H04-330010; JP Kokai H07-285912), glutamic acid derivatives (JP Kokai H07-228561), unsaturated fatty acid derivatives (JP Kokai H08-143454), eudesmane derivatives (JP Kokai H08-73395), condensed-ring oxazole derivatives (JP Kokai H08-175992), carbazole derivatives (JP Kokai H08-169879), indole derivatives (JP Kokai H07-118152; JP Kokai H08-239362), and natural product-derived terpene derivatives (JP Kokai H07-149633; JP Kokai H08-319289). However, their activities are not satisfactory enough, and more potent compounds are desired. It is also known that leteprinim (NeuroTherapeutics, USA), which is a purine derivative, promotes intracranial neurotrophin production in an animal model.
Meanwhile, some of the compounds of the formula (I) or salts thereof described hereafter, wherein X is O, which are active ingredients in the present invention, are disclosed in JP Kokai H09-323983 (WO97/36882), hence already known. However, the neurotrophin production/secretion promoting activity of these known compounds is so far unknown.
It is an object of the present invention to provide neurotrophin production/secretion promoting agents which are useful in the prevention and treatment of diabetic neuropathy, other kinds of peripheral neuropathy resulting from cancer chemotherapy, diabetic cardiomyopathy, nerve degeneration diseases, amyotrophic lateral sclerosis, multiple sclerosis, cerebral ischemic diseases, Alzheimer""s disease, Parkinson""s disease, Huntington""s chorea, depression, inflammatory bowel disease and so forth.
The present inventors found that a specific class of azole derivatives or salts thereof have excellent neurotrophin production/secretion promoting activity and, as a result of further investigations, have now completed the present invention.
Namely, the present invention relates to
(1) a neurotrophin production/secretion promoting agent which comprises an azole derivative of the formula: 
xe2x80x83wherein R1 represents a halogen atom, a heterocyclic group which may optionally be substituted, a hydroxy group which may optionally be substituted, a thiol group which may optionally be substituted, or an amino group which may optionally be substituted; A represents an acyl group which may optionally be substituted, a heterocyclic group which may optionally be substituted, a hydroxy group which may optionally be substituted, or a carboxyl group which may optionally be esterified or amidated; B represents an aromatic group which may optionally be substituted; X represents oxygen atom, sulfur atom, or nitrogen atom which may optionally be substituted; and Y represents a divalent hydrocarbon group or heterocyclic group, or a salt thereof;
(2) a neurotrophin production/secretion promoting agent which comprises a prodrug of an azole derivative or a salt thereof as defined in the above (1);
(3) an agent according to the above (1), wherein R1 is a nitrogen-containing heterocyclic group which may optionally be substituted;
(4) an agent according to the above (1), wherein R1 is an aromatic heterocyclic group which may optionally be substituted;
(5) an agent according to the above (1), wherein R1 is a nitrogen-containing 5-membered aromatic heterocyclic group which may optionally be substituted;
(6) an agent according to the above (1), wherein R1 is an imidazolyl group which may optionally be substituted;
(7) an agent according to the above (1), wherein A is a heterocyclic group which may optionally be substituted, or a hydroxy group which may optionally be substituted;
(8) an agent according to the above (1), wherein A is an aryloxy group which may optionally be substituted;
(9) an agent according to the above (1), wherein A is a phenoxy group substituted with an alkyl group which may optionally be substituted;
(10) an agent according to the above (1), wherein B is a phenyl group which may optionally be substituted;
(11) an agent according to the above (1), wherein Y is a divalent aliphatic hydrocarbon group;
(12) an agent according to the above (1), wherein X is xe2x80x94Oxe2x80x94;
(13) an agent according to the above (1), wherein X is xe2x80x94Sxe2x80x94;
(14) an agent according to the above (1), wherein X is xe2x80x94NR4xe2x80x94 wherein R4 represents a hydrogen atom, a hydrocarbon group which may optionally be substituted, an acyl group which may optionally be substituted, or a heterocyclic group which may optionally be substituted;
(15) an agent according to the above (1), wherein the azole derivative is 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropanol, 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolebutanol, 4-(4-chlorophenyl)-5-[3-(1-imidazolyl)propyl]-2-(2-methyl-1-imidazolyl)oxazole, 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepentanol, 4-(4-chlorophenyl)-5-[4-(1-imidazolyl)butyl]-2-(2-methyl-1-imidazolyl)oxazole, 3-[3-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]propyl]-1-methyl-2,4-imidazolidinedione, 4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]-2-(2-methyl-1-imidazolyl)oxazole, 4-(4-chlorophenyl)-5-[3-(3-methoxyphenoxy)propyl]-2-(2-methyl-1-imidazolyl)oxazole, 4-(4-chlorophenyl)-5-[3-(4-methoxyphenoxy)propyl]-2-(2-methyl-1-imidazolyl)oxazole, or 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl]oxazole;
(16) an agent according to the above (1) which is a prophylactic/therapeutic agent for neuropathy;
(17) an agent according to the above (1) which is a prophylactic/therapeutic agent for peripheral neuropathy;
(18) a thiazole derivative of the formula: 
xe2x80x83wherein R1a represents a heterocyclic group which may optionally be substituted; A represents an acyl group which may optionally be substituted, a heterocyclic group which may optionally be substituted, a hydroxy group which may optionally be substituted, or a carboxyl group which may optionally be esterified or amidated; B represents an aromatic group which may optionally be substituted; and Y represents a divalent hydrocarbon group or heterocyclic group, or a salt thereof;
(19) a prodrug of a thiazole derivative or a salt thereof as defined in the above (18);
(20) a compound according to the above (18), wherein R1a is a nitrogen-containing 5-membered aromatic heterocyclic group which may optionally be substituted;
(21) a compound according to the above (18), wherein R1a is an imidazolyl group which may optionally be substituted;
(22) a compound according to the above (18), wherein A is an aryloxy group which may optionally be substituted;
(23) a compound according to the above (18), wherein B is a phenyl group which may optionally be substituted;
(24) a compound according to the above (18), wherein Y is a divalent aliphatic hydrocarbon group;
(25) a pharmaceutical composition which comprises a thiazole derivative or a salt thereof as defined in the above (18);
(26) a composition according to the above (25) which is a neurotrophin production/secretion promoting agent;
(27) a composition according to the above (25) which is a prophylactic/therapeutic agent for neuropathy;
(28) a composition according to the above (25) which is a prophylactic/therapeutic agent for peripheral neuropathy;
(29) an oxazole derivative of the formula: 
xe2x80x83wherein R1 represents a halogen atom, a heterocyclic group which may optionally be substituted, a hydroxy group which may optionally be substituted, a thiol group which may optionally be substituted, or an amino group which may optionally be substituted; Ab represents an aryloxy group which is substituted by an alkyl group and may further be substituted; B represents an aromatic group which may optionally be substituted; and Y represents a divalent hydrocarbon group or heterocyclic group, or a salt thereof;
(30) a compound according to the above (29), wherein Ab is an aryloxy group which is substituted by an alkyl group;
(31) a prodrug of an oxazole derivative or a salt thereof as defined in the above (29);
(32) a compound according to the above (29), wherein R1 is a nitrogen-containing 5-membered aromatic heterocyclic group which may optionally be substituted;
(33) a compound according to the above (29), wherein R1 is an imidazolyl group which may optionally be substituted;
(34) a compound according to the above (33), wherein R1 is an imidazolyl group which may optionally be substituted by a C1-10 alkyl;
(35) a compound according to the above (29), wherein B is a phenyl group which may optionally be substituted;
(36) a compound according to the above (35), wherein B is a phenyl group which may optionally be substituted by halogens;
(37) a compound according to the above (29), wherein Y is a divalent aliphatic hydrocarbon group;
(38) a compound according to the above (37), wherein Y is a divalent C1-4 aliphatic hydrocarbon group;
(39) a pharmaceutical composition which comprises an oxazole derivative or a salt thereof as defined in the above (29);
(40) a composition according to the above (39) which is a neurotrophin production/secretion promoting agent;
(41) a composition according to the above (39) which is a prophylactic/therapeutic agent for neuropathy;
(42) a composition according to the above (39) which is a prophylactic/therapeutic agent for peripheral neuropathy;
(43) 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl]oxazole or a salt thereof;
(44) a crystal of 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl]oxazole or a salt thereof;
(45) 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(3-methylphenoxy)propyl]oxazole or a salt thereof;
(46) a crystal of 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(3-methylphenoxy)propyl]oxazole or a salt thereof;
(47) 5-[3-(4-chloro-2-methylphenoxy)propyl]-4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)oxazole or a salt thereof;
(48) a crystal of 5-[3-(4-chloro-2-methylphenoxy)propyl]-4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)oxazole or a salt thereof;
(49) a method for promoting neurotrophin production/secretion in a mammal in need thereof, which comprises administering to said mammal an effective amount of an azole derivative or a salt thereof as defined in the above (1);
(50) a method for promoting neurotrophin production/secretion in a mammal in need thereof, which comprises administering to said mammal an effective amount of a thiazole derivative or a salt thereof as defined in the above (18);
(51) a method for promoting neurotrophin production/secretion in a mammal in need thereof, which comprises administering to said mammal an effective amount of an oxazole derivative or a salt thereof as defined in the above (29);
(52) a method for preventing or treating neuropathy in a mammal in need thereof, which comprises administering to said mammal an effective amount of a thiazole derivative or a salt thereof as defined in the above (18);
(53) a method for preventing or treating neuropathy in a mammal in need thereof, which comprises administering to said mammal an effective amount of an oxazole derivative or a salt thereof as defined in the above (29);
(54) use of an azole derivative or a salt thereof as defined in the above (1) for the manufacture of a neurotrophin production/secretion promoting agent;
(55) use of a thiazole derivative or a salt thereof as defined in the above (18) for the manufacture of a neurotrophin production/secretion promoting agent;
(56) use of an oxazole derivative or a salt thereof as defined in the above (29) for the manufacture of a neurotrophin production/secretion promoting agent;
(57) use of a thiazole derivative or a salt thereof as defined in the above (18) for the manufacture of a pharmaceutical preparation for preventing or treating neuropathy;
(58) use of an oxazole derivative or a salt thereof as defined in the above (29) for the manufacture of a pharmaceutical preparation for preventing or treating neuropathy; etc.